This project is concerned with the biochemistry and genetics of heritable diseases of amino acid and organic acid metabolism. The diseases which will be studied most intensively are nonketotic hyperglycinemia, propionic acidemia, and biotin-responsive combined 3-methylcrotonylglycinuria and propionic acidemia. It is devoted to the detection and definition of new metabolic diseases and the study of metabolic interactions in these and other metabolic disorders. Emphasis is on identifying elevated or abnormal metabolites and relating them to the pathogenesis of the clinical disease. Characterization of defective or variant enzymes responsible for the altered metabolism is an integral part of the project. The knowledge gained from these studies is of importance in diagnosis and possible treatment of these inherited diseases. These studies are also providing considerable information about the quantitative and qualitative importance of metabolic pathways in normal humans.